Effect of hydrophobic and hydrogen bonding interactions on the potency of ß‐alanine analogs of G‐protein coupled glucagon receptor inhibitors

2019 ◽  
Vol 88 (2) ◽  
pp. 327-344 ◽  
Author(s):  
Pushyaraga P. Venugopal ◽  
Bratin K. Das ◽  
E. Soorya ◽  
Debashree Chakraborty
Keyword(s):  
Hydrogen Bonding ◽  
G Protein ◽  
Glucagon Receptor ◽  
Hydrogen Bonding Interactions ◽  
G Protein Coupled

Activation and conformational dynamics of a class B G-protein-coupled glucagon receptor

2016 ◽  
Vol 18 (18) ◽  
pp. 12642-12650 ◽  
Author(s):  
Yang Li ◽  
Jixue Sun ◽  
Dongmei Li ◽  
Jianping Lin
Keyword(s):  
Hydrogen Bonds ◽  
G Protein ◽  
Conformational Dynamics ◽  
Glucagon Receptor ◽  
Class B ◽  
G Protein Coupled

The binding of the agonist glucagon would induce the conformational dynamics and activation of the GCGR. The activation led to the outward movement of helix VII and breaking of two hydrogen bonds.

scholarly journals Interaction of Glucagon G-Protein Coupled Receptor with Known Natural Antidiabetic Compounds: MultiscoringIn SilicoApproach

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
M. H. Baig ◽  
K. Ahmad ◽  
Q. Hasan ◽  
M. K. A. Khan ◽  
N. S. Rao ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
Scoring Function ◽  
Natural Compounds ◽  
G Protein Coupled Receptors ◽  
Binding Potential ◽  
Glucagon Receptor ◽  
Class B ◽  
G Protein Coupled

Glucagon receptor (GCGR) is a secretin-like (class B) family of G-protein coupled receptors (GPCRs) in humans that plays an important role in elevating the glucose concentration in blood and has thus become one of the promising therapeutic targets for treatment of type 2 diabetes mellitus. GCGR based inhibitors for the treatment of type 2 diabetes are either glucagon neutralizers or small molecular antagonists. Management of diabetes without any side effects is still a challenge to the medical system, and the search for a new and effective natural GCGR antagonist is an important area for the treatment of type 2 diabetes. In the present study, a number of natural compounds containing antidiabetic properties were selected from the literature and their binding potential against GCGR was determined using molecular docking and otherin silicoapproaches. Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin. These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from the GOLD andx-score. Further experiments were conducted to identify the atomic level interactions of selected compounds with GCGR.

scholarly journals The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activlation

2022 ◽  
Vol 12 ◽  
Author(s):  
Ian Winfield ◽  
Kerry Barkan ◽  
Sarah Routledge ◽  
Nathan J. Robertson ◽  
Matthew Harris ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Cgrp Receptor ◽  
Intracellular Loop ◽  
Glucagon Receptor ◽  
G Protein Coupled

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

scholarly journals A combined activation mechanism for the glucagon receptor

2020 ◽  
Vol 117 (27) ◽  
pp. 15414-15422
Author(s):  
Giulio Mattedi ◽  
Silvia Acosta-Gutiérrez ◽  
Timothy Clark ◽  
Francesco Luigi Gervasio
Keyword(s):  
G Protein ◽  
Receptor Agonist ◽  
Structural Data ◽  
Activation Mechanism ◽  
Glucagon Receptor ◽  
Gpcr Activation ◽  
Class B ◽  
G Protein Coupled ◽  
Conformational Free Energy ◽  
Important Drug

We report on a combined activation mechanism for a class B G-protein–coupled receptor (GPCR), the glucagon receptor. By computing the conformational free-energy landscape associated with the activation of the receptor–agonist complex and comparing it with that obtained with the ternary complex (receptor–agonist–G protein) we show that the agonist stabilizes the receptor in a preactivated complex, which is then fully activated upon binding of the G protein. The proposed mechanism contrasts with the generally assumed GPCR activation mechanism, which proceeds through an opening of the intracellular region allosterically elicited by the binding of the agonist. The mechanism found here is consistent with electron cryo-microscopy structural data and might be general for class B GPCRs. It also helps us to understand the mode of action of the numerous allosteric antagonists of this important drug target.

Lateral Allosterism in the Glucagon Receptor Family: Glucagon-Like Peptide 1 Induces G-Protein-Coupled Receptor Heteromer Formation

2011 ◽  
Vol 81 (3) ◽  
pp. 309-318 ◽  
Author(s):  
Dominik Schelshorn ◽  
Fanny Joly ◽  
Sophie Mutel ◽  
Cornelia Hampe ◽  
Billy Breton ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Glucagon Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled ◽  
Receptor Family

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

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